In 2013 the European commission licensed 4CMenB, a multicomponent vaccine developed to protect against serogroup B meningococcal (MenB) disease, for use from 2 months of age onwards.1 4CMenB contains an outer membrane vesicle (OMV) from the New Zealand epidemic strain, NZ98/254, along with 3 other proteins and is a potential candidate for routine infant immunization. Various European countries are currently assessing the potential for use of the vaccine in their routine vaccination schedules. Important considerations in making the decision to implement a new vaccine are cost-effectiveness assessments and duration of protection has a key input into these calculations.
Previous studies have demonstrated that 4CMenB induces serum bactericidal antibodies with exogenous human complement (hSBA) against MenB indicator strains under a variety of different infant schedules.2–5 An increase in bactericidal antibodies is noted after a booster dose of this vaccine given at 40 months of age.6 However, there are limited data on the persistence of these antibodies, which are needed to inform on the potential protection of children through their primary school years.
Here, we report the results of an extension study investigating the persistence of hSBA against a panel of MenB indicator strains in 5-year-old children previously immunized against MenB. In the original study, infants were randomized to receive 1 of 2 MenB vaccines, either 4CMenB or rMenB, a different investigational vaccine that lacks the OMV component of 4CMenB.2 Both groups received their respective vaccines at 6, 8, 12 and 40 months of age. In the first part of the extension study, a third group was recruited who received only 4CMenB at 40 and 42 months of age.6 In the second part of the extension study, we investigated these 3 previous groups. In addition, we evaluated the immunogenicity and reactogenicity of 4CMenB given to MenB vaccine-naïve children at 60 and 62 months of age, thus informing any “catch-up” program involving this age group that could accompany the potential introduction of 4CMenB.
MATERIALS AND METHODS
This was a phase 2, open-label, single-centre extension of a randomized control trial that ran from 2010 to 2012. The study was approved by the Oxfordshire Research Ethics Committee (Ref: 09/H0605/89).
The 4CMenB vaccine (Bexsero, Novartis Vaccines and Diagnostics) contained 50 μg NadA protein 3, 50 μg NHBA-GNA1030 fusion protein (containing NHBA peptide 2), 50 μg GNA2091-fHbp fusion protein (containing fHbp variant 1.1) and 25 μg detoxified outer membrane vesicles from N. meningitides strain NZ98/254 (expressing PorA serosubtype P1.4). The vaccine also contained 1.5 mg aluminum hydroxide. All vaccines were 0.5 mL in volume and were administered into the deltoid muscle of the nondominant arm.
Within the original infant study, 1 group (rMenB infancy) received the alternative vaccine, rMenB which contained 50 μg NadA protein 3, 50 μg NHBA-GNA1030 fusion protein (containing NHBA peptide 2) and 50 μg GNA2091-fHbp fusion protein (containing fHbp variant 1.1), but lacked the OMV component of 4CMenB.
In the original infant study,2 1 group of children (4CMenB infancy) were vaccinated at 6, 8 and 12 months of age with 4CMenB and a second group (rMenB infancy) received the rMenB vaccine using the same schedule. The first part of the extension study investigated persistence of antibodies in these children at 40 months and included the administration of a booster dose of the same vaccine given previously. A third group of children (4CMenB 40m) was recruited and received 2 “catch-up” doses of 4CMenB at approximately 40 and 42 months of age.6 The second stage of the extension study, reported here, followed up the 3 previous groups and also recruited a fourth group of children (4CMenB 60m) aged approximately 5 years from the Thames Valley area.
Children with a history of meningococcal disease (or intimate contact with a confirmed case) or previous MenB vaccination (outside the original study) were excluded. No other vaccines were permitted within 30 days before or after receiving 4CMenB. Other exclusion criteria included: a history of allergy to the vaccine or its components, any chronic/progressive disease or immune suppression including systemic steroid use, receipt of blood or immunoglobulin in the last 90 days and family members of research staff. Participants were temporarily excluded if they had been febrile (>38°C) in the last 24 hours or had had a significant infection in the past week. Before initial study procedures all enrolled participants had a brief medical check by a physician.
The study procedures are summarized in Figure (Supplemental Digital Content 1, http://links.lww.com/INF/B859). All children had a 5 mL blood drawn at approximately 60 months of age. The vaccine naïve 4CMenB 60m group then received 2 doses of 4CMenB, 2 months apart, followed by a second blood draw 1 month after the final dose.
Blood samples were analyzed for serum bactericidal antibodies using human complement (hSBA) at Novartis laboratories (Marburg, Germany). An hSBA titer of ≥1:4 was used as a correlate of protection against the indicator strains.7
The indicator strains were chosen to assess the immunogenicity of each of the 4 components of the 4CMenB vaccine listed above. Strain 44/76-SL was used to assess the response to the factor H binding protein component, 5/99 to indicate response to NadA, NZ98/254 to PorA (the dominant antigen in OMV) and M10713 to NHBA. As in the earlier studies,2,6 4 additional strains were also tested to assess the effect of antigenic variation. Details regarding strain selection have been previously described.2
Safety Data and Reactogenicity
Reactogenicity and safety data were solicited for 7 days after vaccination using paper diary cards. Parents were instructed to record daily axillary temperature, local reactions to vaccination (pain, erythema, induration and swelling) and specified systemic symptoms. Solicited symptoms were graded as mild, moderate and severe in terms of number of meals missed (change in appetite), restriction to normal activity (pain, sleepiness, irritability, headache and arthralgia) or number of episodes (diarrhea and vomiting). Temperature, erythema, induration and swelling were also categorized as mild (38–38.9°C, 1–25 mm) moderate (39–39.9°C, 25–50 mm) or severe (>40°C or >50 mm) based on objective measurements. Medically attended and serious adverse events were recorded throughout the study. A judgment was made by study investigators as to whether the adverse event was possibly, probably or not related.
The primary objective of the extension study was to investigate hSBA persistence to 40 months of age, as has been reported elsewhere.6 Here, we consider the secondary objectives that were to explore the persistence of antibody at 60 months of age in children who had previously received either rMenB or 4CMenB vaccination and to evaluate antibody response in vaccine-naïve subjects given 4CMenB at 60 and 62 months of age. The percentage of children with hSBA titers ≥ 1:4 was calculated for each group and each blood sampling visit, as were the hSBA geometric mean titers (GMTs). Antibody data were log10 transformed for analysis. The secondary safety objective was to assess the safety and tolerability of a 2-dose catch-up regimen at 60 months of age.
The numbers of children participating at each stage are summarized in Figures (Supplemental Digital Content 1 and 2, http://links.lww.com/INF/B859 and http://links.lww.com/INF/B860). Twenty-five children who had been enrolled at 40 months of age did not participate at 60 months. Of these, 18 were lost to follow up at some point between 40 and 60 months and 7 had been withdrawn at the 40 months stage, most commonly because of distress at blood tests. The groups were similar in terms of sex and ethnicity with the exception of the 4CMenB infancy group that contained more females (11 females and 3 males). Overall, 86% of participants were Caucasian, 5% Asian, 4% Black and 5% other.
All children from the rMenB infancy, 4CMenB infancy and 4CMenB 40m groups who provided samples at 60 months were included and comparisons are descriptive. Immunogenicity results for the 4CMenB 60m group were analyzed on a modified intention to treat basis, that is, all participants who received at least 1 dose of 4CMenB and provided at least 1 evaluable serum sample. All children in the 4CMenB 60m group who received at least 1 dose of 4CMenB and provided safety data were included in the safety analysis.
Persistence of Bactericidal Antibodies
The percentage of children with hSBA titers ≥1:4 for the indicator strains are shown in Table 1 and hSBA GMTs in Table 2. Figure 1 shows the hSBA GMT results across the original study, follow up at 40 and 60 months. With the exception of strain 5/99 (testing response to NadA), where bactericidal antibodies persisted in 100% of participants, the percentage of children with protective titers waned, most notably for the NZ98/254 (PorA) strain, against which titers fell from 90% to 0% in the 4CMenB 40m group and from 93% to 17% among those receiving 4CMenB in infancy. As expected, rMenB without OMV remained poorly immunogenic for this strain.
When compared with the preimmunization control children, those who had previously been immunized with 4CMenB were more likely to have hSBA titers ≥1:4 for strains 44/76-SL (fHbp) and 5/99 (NadA; non-overlapping confidence intervals) at 60 months of age. However, for strains NZ98/254 (PorA) and M10713 (NHBA), the proportions with titers above this threshold were very similar between 4CMenB immunized and naive groups. The 95% confidence intervals for hSBA GMTs also overlapped for these strains.
Response to Vaccination at 60 Months of Age
A 2-dose schedule of 4CMenB was immunogenic for children aged 60 months with hSBA titers ≥1:4 one month postimmunization of between 68% and 100% depending on the strain (Table 1).
Reactogenicity at 60 Months of Age
All children who were vaccinated at 60 months reported at least 1 solicited adverse reaction. All experienced at least 1 local reaction after with 91–92% (after immunizations 1 and 2, respectively) reporting pain, which was severe (unable to perform normal activities) in 10–13% (Fig., Supplemental Digital Content 3, http://links.lww.com/INF/B861). Pain was maximal between 6 hours and 1 day postimmunization and was present at day 7 in 19%, although no severe pain was reported after day 3 (Fig., Supplemental Digital Content 4, http://links.lww.com/INF/B862). Other local reactions were also experienced by many participants (Fig., Supplemental Digital Content 3, http://links.lww.com/INF/B861).
Ninety-two percent of participants experienced a systemic reaction at some point in the 7 days postvaccination. Ten percent experienced fever >38°C after the first immunization and 11% after the second (Fig., Supplemental Digital Content 5, http://links.lww.com/INF/B863), mostly within the first 24 hours after vaccination (data not shown), but no temperature above 39.5°C was recorded. No fever required medical attendance.
There were 3 withdrawals in the 4CMenB 60m group. One participant withdrew consent before any study procedures and 2 withdrew after the first vaccination. Of these 2, 1 withdrew after an urticarial rash judged to be possibly related to the vaccine (although the participant also had a concurrent viral infection). There was a serious adverse event involving hospitalization because of an exacerbation of asthma 15 days after the second immunization. The participant was known to have asthma before enrolment and the event was not considered to be related to the vaccine.
These results show that even with an additional booster dose at 40 months of age, children immunized as infants with a 3 dose schedule at 6, 8 and 12 months have variable waning of bactericidal antibodies by 5 years of age. This was also noted in those immunized for the first time with 2 doses at 40 and 42 months of age. The decrease in percentage of children with antibody titers above the putative protective threshold appeared to be strain, and therefore vaccine antigen, specific with the greatest decline in immunity for strain NZ98/254 [PorA; 0% and 17% at 20 months after primary (2 doses) and booster dose of 4CMenB, respectively, given to 40-month-old children], whereas protection against strain 5/99 (NadA) was fully maintained. In addition, it is worth noting that many vaccine naïve children had baseline hSBA titers ≥ 1:4 against M10713 (NHBA), suggesting that there may be natural acquisition of immunity against M10713 with age, although this could also be an indication that M10713 is particularly sensitive to killing within the assay.8 A similar decline in antibodies after immunization with OMV vaccines has been reported previously in New Zealand and Norway9,10 and is in line with experience of the serogroup C meningococcal (MenC) vaccine.11,12 For the multicomponent 4CMenB vaccine, however, the significance of differential waning of response to antigens on length of protection is currently not clear. Although hSBA titers ≥1:4 are the correlate of protection against strains expressing these specific antigens, it is not known how protection against these vaccine antigens correlates with immunity against the heterologous range of natural pathogens. Vogel et al13 found that a much higher proportion of isolates were predicted to be covered by the fHbp and NHBA antigens compared with NadA; therefore, the more impressive persistence observed against the 5/99 strain, which assesses NadA, may not equate to long-term protections against MenB disease in general.
In contrast to the introduction of immunization against MenC in the United Kingdom in 1999, the UK Joint Committee on Vaccination and Immunization in its “Interim Position Statement on use of the 4CMenB vaccine in the UK” has not yet recommended the introduction of 4CMenB, with cost-effectiveness a key barrier to its implementation.14 Despite evidence of waning immunity after MenC vaccination,12,15–17 which has resulted in changes to the vaccination schedule over the years,11 vaccination against MenC has been extremely effective, and MenB now accounts for over 80% of meningococcal cases in the United Kingdom.18 Determining the duration of protection of the 4CMenB vaccine seems to be much more complicated than for MenC vaccines because of the variable waning against the different vaccine antigens. The persistence of immunity for some vaccine antigens is more promising than for MenC, whereas it seems similar or less for other antigens.15,16,19 However, because the significance of differential waning of antibody on the persistence of immunity to vaccine antigens is currently unknown, it is difficult to predict coverage over time. The variable waning by antigen is likely to further complicate cost-effectiveness models, which are based on assumptions of consistent waning of immunity against all strains.20 However, such data that are presented in this manuscript are informative for the development of a cost-effectiveness assessment.
Assessing strain coverage has been a challenge in MenB vaccine development. Measurement of hSBA has been established as a surrogate measure of protection,21 but cannot be used to assess every strain because of the limited volume of serum available, especially in pediatric studies.13,22 Invasive meningococcal disease remains rare with an overall UK incidence of 2 in 100,000 of which MenB is responsible for 87%,23 therefore randomized controlled studies looking at clinical outcomes are not feasible. An assay developed by the manufacturer of 4CMenB in collaboration with European national reference laboratories to predict strain coverage, the meningococcal antigen typing system, has estimated that 4CMenB would provide protection against 66% of strains in Canada, 73% in the United Kingdom and 78% Europe wide.13,24 However, recent data suggest that this is a conservative estimate and coverage may be as high as 88 %.25 In addition, mathematical models suggest that introducing a MenB vaccine into the infant schedule with a catch-up campaign would reduce the number of cases per year20 but may or may not be cost-effective depending on the input parameters of the model.14 Ultimately, the clinical significance of introducing the 4CMenB vaccine in terms of number of cases, mortality and morbidity will not become clear until large scale epidemiological studies are undertaken after the vaccine is introduced.26
Waning immunity before the age of 5 years is particularly important as the incidence of MenB disease remains higher in 1- to 4-year-old children, second only to that of children <1 year.23,27 These data suggest that by the time children immunized in infancy or at 40 months enter primary school they may no longer have immunity to a number of MenB strains and this vulnerability is therefore likely to extend into adolescence. Further follow-on studies will be required to assess whether this is also true for those immunized at 60 months. This is of particular interest because MenB disease has a second smaller peak in late teenage years,18,23 therefore these results give an early indication that an adolescent booster may be required. A similar conclusion has been reached regarding MenC vaccines and an adolescent MenC booster is due to be introduced into the UK schedule in the autumn of 2013.11 An alternative approach, such as that suggested within the recent Joint Committee on Vaccination and Immunization statement, could be to immunize only adolescents and rely on herd immunity. Data on bactericidal antibody persistence over a similar period to this study have been published for adolescents vaccinated with 1–3 doses of 4CMenB and seems to show more durable response than the Joint Committee on Vaccination and Immunization findings of this study in terms of both percentage with hSBA ≥1:4 and GMTs.28 However, although currently there is suggestive data that this vaccine may induce herd immunity,29 in the absence of definitive evidence, it is important to directly protect infants who are at highest risk of invasive disease. The potential effect of a more mature immune system has also been observed in this study in the postvaccination increase in GMT for strain GB355 that was much greater than that observed previously in the younger age groups (Figure 1).
Although it is one of the licensed indications,1 the 6, 8 and 12 months schedule used in this study is unlikely to be implemented in the United Kingdom, except in the context of a catch-up campaign or epidemic, in part because of the relatively high incidence of meningococcal disease before 6 months of age.23 4CMenB has been licensed for use as a 2-dose catch-up regimen from 6 months of age to adulthood and the evidence presented here that a 2-dose catch-up schedule at 60 months induces protective hSBAs supports this indication. A booster dose is recommended in the second year of life for those immunized between 6 and 11 months and at 1–2 years after the primary series for those immunized between 12 and 23 months.1 However, the need for boosters beyond the age of 2 years has yet to be established and these findings suggest more work needs to be done to ensure children remain protected throughout their primary school years after infant vaccination.
In view of a potential catch-up campaign, the reactogenicity data are of particular relevance. In particular, pain postimmunization was an important issue affecting almost all participants. Approximately half the children had at least some limitation in performing normal activities and 11% were unable to perform normal activities for 24 hours postvaccination. Although severe pain was minimal after this period, some level of pain was reported for at least 7 days after the vaccine was administered in about 1 of 5 subjects. The original infant studies recorded lower levels of injection site tenderness with 4CMenB (9–11%, in Snape et al2 and 30–50% in Findlow et al3), but similar high percentages to this study were reported by those immunized at 40 months.6 However, it is also important to note that in the infant studies the vaccine was administered into the thigh rather than the deltoid muscle of the arm. Another explanation could be that the older children were more able to vocalize their discomfort and remembered the immunization event. Nevertheless, the percentage of children reporting pain in this study seems higher than that seen in other trials of preschool vaccines, such a studies of DTPa-IPV in which around 63% of 5–6 years of age reported injection site pain30 or measles-mumps-rubella/measles, mumps, rubella and varicella vaccines in which 58–73% of 6 years of age reported pain.31 As these reactions were solicited, they may not have been otherwise reported, however, the level of pain may have implications in terms of school and nursery attendance in this age group and parents should be counseled to expect their child to complain of a painful arm. Increased rates of injection site pain were also reported after 4CMenB in adolescents in a large scale, placebo-controlled study in Chile32 and in adult laboratory workers.33 This observation is in line with reports after other OMV-containing meningococcal vaccines, such as the MenBvac and MeNZB used in the Norwegian and New Zealand epidemics.34
The fever rates of around 10% for children immunized at 60 and 62 months were similar to those seen in the infant and 40 month studies2,6 and lower than those seen in the DTPa-IPV study referred to above in which axillary temperature over 38°C was observed in around 20% of 5- to 6-year-old participants.30 The lack of medically attended fever indicates that this is a symptom with which parents are familiar and feel able to cope with at home. Effective communication and advice to the parents, including the appropriate use of paracetamol,18 may also help to alleviate concerns.
This study is limited because of relatively small sample sizes. Only about one-third of the children from the original infant study and just over half of those immunized at 40 months participated in the 60 month follow on. Limited data are available for those who did not take part in the follow-up studies as the majority were lost to follow up. Most children were Caucasian and all lived in Oxfordshire or the surrounding counties; therefore, it may not be appropriate to generalize these findings to children outside this population. MenB epidemiology and strain prevalence varies worldwide35 therefore the MenB exposure of both immunized and control children in this study may vary from that experienced by children in different geographical locations. Nevertheless, the data presented here do suggest waning titers of bactericidal antibodies induced by immunization with 4CMenB according to a licensed schedule of 6, 8 and 12 months of age, even with an extra booster dose at 40 months of age. Local reactogenicity of the 2 dose schedule administered in 5-year-old children is of concern and warrants further assessment. In particular, the increased risk of fever and pain at the injection site would need to be communicated to the infant’s or child’s family before administration.
In conclusion, these data add useful information on the length of protection afforded by 4CMenB but how best to interpret the breadth of protection remains unclear and has important implications for countries currently debating whether to introduce the vaccine into their routine infant schedules. In particular, the variable waning by antigen complicates predictions of duration, and because killing is predicted to occur based on antibodies targeting a single vaccine antigen, this should be taken into account in cost-effectiveness analyses.
2. Snape MD, Dawson T, Oster P, et al. Immunogenicity of two investigational serogroup B meningococcal vaccines in the first year of life: a randomized comparative trial. Pediatr Infect Dis J. 2010;29:e71–e79
3. Findlow J, Borrow R, Snape MD, et al. Multicenter, open-label, randomized phase II controlled trial of an investigational recombinant Meningococcal serogroup B vaccine with and without outer membrane vesicles, administered in infancy. Clin Infect Dis. 2010;51:1127–1137
4. Vesikari T, Esposito S, Prymula R, et al.EU Meningococcal B Infant Vaccine Study group. Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials. Lancet. 2013;381:825–835
5. Gossger N, Snape MD, Yu LM, et al.European MenB Vaccine Study Group. Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial. JAMA. 2012;307:573–582
6. Snape MD, Philip J, John TM, et al. Bactericidal antibody persistence 2 years after immunization with 2 investigational serogroup B meningococcal vaccines at 6, 8 and 12 months and immunogenicity of preschool booster doses: a follow-on study to a randomized clinical trial. Pediatr Infect Dis J. 2013;32:1116–1121
7. Borrow R, Carlone GM, Rosenstein N, et al. Neisseria meningitidis group B correlates of protection and assay standardization–international meeting report Emory University, Atlanta, Georgia, United States, 16–17 March 2005. Vaccine. 2006;24:5093–5107
8. Martin NG, Snape MD. A multicomponent serogroup B meningococcal vaccine is licensed for use in Europe: what do we know, and what are we yet to learn? Expert Rev Vaccines. 2013;12:837–858
9. Jackson C, Lennon D, Wong S, et al. Antibody persistence following MeNZB vaccination of adults and children and response to a fourth dose in toddlers. Arch Dis Child. 2011;96:744–751
10. Holst J, Feiring B, Fuglesang JE, et al. Serum bactericidal activity correlates with the vaccine efficacy of outer membrane vesicle vaccines against Neisseria meningitidis serogroup B disease. Vaccine. 2003;21:734–737
11. Pollard AJ, Green C, Sadarangani M, et al. Adolescents need a booster of serogroup C meningococcal vaccine to protect them and maintain population control of the disease. Arch Dis Child. 2013;98:248–251
12. Ishola DA Jr, Borrow R, Findlow H, et al. Prevalence of serum bactericidal antibody to serogroup C Neisseria meningitidis in England a decade after vaccine introduction. Clin Vaccine Immunol. 2012;19:1126–1130
13. Vogel U, Taha MK, Vazquez JA, et al. Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment. Lancet Infect Dis. 2013;13:416–425
15. Perrett KP, Winter AP, Kibwana E, et al. Antibody persistence after serogroup C meningococcal conjugate immunization of United Kingdom primary-school children in 1999-2000 and response to a booster: a phase 4 clinical trial. Clin Infect Dis. 2010;50:1601–1610
16. Snape MD, Kelly DF, Green B, et al. Lack of serum bactericidal activity in preschool children two years after a single dose of serogroup C meningococcal polysaccharide-protein conjugate vaccine. Pediatr Infect Dis J. 2005;24:128–131
17. Trotter CL, Borrow R, Findlow J, et al. Seroprevalence of antibodies against serogroup C meningococci in England in the postvaccination era. Clin Vaccine Immunol. 2008;15:1694–1698
19. Borrow R, Andrews N, Findlow H, et al. Kinetics of antibody persistence following administration of a combination meningococcal serogroup C and haemophilus influenzae type b conjugate vaccine in healthy infants in the United Kingdom primed with a monovalent meningococcal serogroup C vaccine. Clin Vaccine Immunol. 2010;17:154–159
20. Christensen H, Hickman M, Edmunds WJ, et al. Introducing vaccination against serogroup B meningococcal disease: an economic and mathematical modelling study of potential impact. Vaccine. 2013;31:2638–2646
21. Frasch CE, Borrow R, Donnelly J. Bactericidal antibody is the immunologic surrogate of protection against meningococcal disease. Vaccine. 2009;27(suppl 2):B112–B116
22. Gorringe AR, Pajón R. Bexsero: a multicomponent vaccine for prevention of meningococcal disease. Hum Vaccin Immunother. 2012;8:174–183
23. Ladhani SN, Flood JS, Ramsay ME, et al. Invasive meningococcal disease in England and Wales: implications for the introduction of new vaccines. Vaccine. 2012;30:3710–3716
24. Bettinger JA, Scheifele DW, Halperin SA, et al.members of the Canadian Immunization Monitoring Program, Active (IMPACT). Diversity of Canadian meningococcal serogroup B isolates and estimated coverage by an investigational meningococcal serogroup B vaccine (4CMenB). Vaccine. 2013;32:124–130
25. Frosi G, Biolchi A, Lo Sapio M, et al. Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS underestimates 4CMenB vaccine strain coverage. Vaccine. 2013;31:4968–4974
26. Snape MD, Medini D, Halperin SA, et al. The challenge of post-implementation surveillance for novel meningococcal vaccines. Vaccine. 2012;30(suppl 2):B67–B72
27. Health Protection Agency.. Invasive Meningococcal B infections laboratory reports England and Wales by age group and epidemiological year 1998/99–2011/12. Updated September 12, 2012. Available at: http://www.hpa.org.uk
. Accessed April 29, 2013
28. Santolaya ME, O’Ryan M, Valenzuela MT, et al. Persistence of antibodies in adolescents 18-24 months after immunization with one, two, or three doses of 4CMenB meningococcal serogroup B vaccine. Hum Vaccin Immunother. 2013;9
29. Read R, Baxter D, Chadwick D, et al. Impact of a quadrivalent conjugate (MenACWY CRM) or a serogroup B (4CMenB) meningococcal vaccine on meningococcal carriage in English university students
2013Meningitis Research Foundation Conference
30. Ferrera G, Cuccia M, Mereu G, et al. Booster vaccination of pre-school children with reduced-antigen-content diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine co-administered with measles-mumps-rubella-varicella vaccine: a randomized, controlled trial in children primed according to a 2 + 1 schedule in infancy. Hum Vaccin Immunother. 2012;8:355–362
31. Vesikari T, Baer M, Willems P. Immunogenicity and safety of a second dose of measles-mumps-rubella-varicella vaccine in healthy children aged 5 to 6 years. Pediatr Infect Dis J. 2007;26:153–158
32. Santolaya ME, O’Ryan ML, Valenzuela MT, et al.V72P10 Meningococcal B Adolescent Vaccine Study group. Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study. Lancet. 2012;379:617–624
33. Kimura A, Toneatto D, Kleinschmidt A, et al. Immunogenicity and safety of a multicomponent meningococcal serogroup B vaccine and a quadrivalent meningococcal CRM197 conjugate vaccine against serogroups A, C, W-135, and Y in adults who are at increased risk for occupational exposure to meningococcal isolates. Clin Vaccine Immunol. 2011;18:483–486
34. Nøkleby H, Aavitsland P, O’Hallahan J, et al. Safety review: two outer membrane vesicle (OMV) vaccines against systemic Neisseria meningitidis serogroup B disease. Vaccine. 2007;25:3080–3084
35. Hoiseth SK, Murphy E, Andrew L, et al. A multi-country evaluation of Neisseria meningitidis serogroup B factor H-binding proteins and implications for vaccine coverage in different age groups. Pediatr Infect Dis J. 2013;32:1096–1101
Serogroup B meningococcus; vaccine; persistence; reactogenicity
© 2014 by Lippincott Williams & Wilkins, Inc.